1. Field of the Invention
This invention relates to a mammal in which production of the protein encoded by the endogenous gene for osteoprotegerin (OPG) has been completely suppressed.
2. Description of Related Art
Osteoprotegerin (OPG) was recently cloned and characterized as a novel member of the TNFR family that is capable of increasing bone density (Simonet et al. Cell 89, 309-319 (1997) and PCT Application No. US96/20621). By blocking a terminal step in the differentiation and/or activation of osteoclasts from their precursors, OPG is one of several factors with the ability to offset the tight coupling between bone resorption and formation. Administration of recombinant OPG to normal mice or ovariectomized rats results in an increase in bone mass and a decrease in bone resorption. OPG is expressed in cartilage rudiments of developing mouse embryos indicating it may be a physiological regulator of the ossification process.
Overexpression of OPG in transgenic mice resulted in severe osteopetrosis associated with a decrease in osteoclast number and activity in metaphyseal trabecular bone (Simonet et al. supra). The phenotype of OPG transgenic mice differs markedly from other murine models of osteopetrosis. Genetic mutants such as op/op mice (csf- 1.sup.-/-) (Yoshida et al. Nature 345:442-444 (1990); Wiktor-Jedrzejczak et al. Proc. Natl. Acad.Sci. USA 87:4828-4832 (1990); Marks et al. J. Heredity 67:11-18 (1976); Wiktor-Jedrzejczak et al. J.Exp. Med. 156:1516-1527 (1982)), microphthalmic mice (mi/mi) (Ebi et al. Blood 75:1247-1251 (1990), Graves et al. J. Cell. Phys. 145:102-109 (1990); Silvers The coat colors of mice: A model for mammalian gene action and interaction. Springer-Verlag, New York, (1979), Isozaki et al. Am. J. Path. 145:827-836 (1994)), and c-src.sup.-/- and c-fos.sup.-/- mice (Soriano et al. Cell 64:693-702 (1991), Wang et al. Nature 3:741-745 (1992), Grigoriadis et al. Science 266:443-448 (1994), Johnson et al. Cell 71:577-586 (1992)) all exhibit osteopetrosis accompanied by impaired tooth eruption and retarded growth. The defects in these genetic mutants are generally associated with decreased bone resorption attributable to decreased osteoclast numbers or inactive osteoclasts (Yoshida et al. supra, Wiktor-Jedrzejczak et al., supra; Graves et al., supra; Grigoriadis et al., supra; Boyce et al. J. Clin. Invest. 90:1622-1627 (1992), Lowe et al. Proc. Natl. Acad. Sci. USA 90:4485-4489 (1993)). In general, the long bones of the characterized osteopetrotic mouse models are shortened in length and the mice exhibit modest facial and cranial abnormalities. Osteopetrosis in OPG transgenic founder animals was severe in high expressors, yet occurred without shortening of the long bones or impaired tooth eruption (Simonet et al., supra).
It has been established that pharmacological doses of OPG result in increased bone density. However, there is a need to understand the physiological role of OPG in the development and maintenance of bone mass and other metabolic processes. In particular, there is a need to determine whether OPG is a physiological regulator of bone mass, and whether other factors can compensate to maintain normal bone mass in its absence. Further, an animal model in which bone density is decreased would be valuable for screening novel therapeutics for diseases of bone loss.
Accordingly, it is an object of this invention to provide a mammal in which the gene encoding OPG has been suppressed.
This and other such objects will readily be apparent to one of ordinary skill in the art.